Orexin is a neurotransmitter that regulates wakefulness and appetite. Orexins are excitatory neuropeptides that have a critical role in maintaining wakefulness. Orexin receptors are found in the mammalian brain and may have numerous implications in pathologies such as depression; anxiety; addictions; obsessive compulsive disorder; affective neurosis; depressive neurosis; anxiety neurosis; dysthymic disorder; behavior disorder; mood disorder; sexual dysfunction; psychosexual dysfunction; sex disorder; schizophrenia; manic depression; delirium; dementia; severe mental retardation and dyskinesias such as Huntington's disease and Tourette syndrome; eating disorders such as anorexia, bulimia, cachexia, and obesity; addictive feeding behaviors; binge/purge feeding behaviors; cardiovascular diseases; diabetes; appetite/taste disorders; emesis, vomiting, nausea; asthma; cancer; Parkinson's disease; Cushing's syndrome/disease; basophile adenoma; prolactinoma; hyperprolactinemia; hypophysis tumor/adenoma; hypothalamic diseases; inflammatory bowel disease; gastric dyskinesia; gastric ulcers; Froehlich's syndrome; adenohypophysis disease; hypophysis disease; adenohypophysis hypofunction; adenohypophysis hyperfunction; hypothalamic hypogonadism; Kallman's syndrome (anosmia, hyposmia); functional or psychogenic amenorrhea; hypopituitarism; hypothalamic hypothyroidism; hypothalamic-adrenal dysfunction; idiopathic hyperprolactinemia; hypothalamic disorders of growth hormone deficiency; idiopathic growth deficiency; dwarfism; gigantism; acromegaly; disturbed biological and circadian rhythms; sleep disturbances associated with diseases such as neurological disorders, neuropathic pain and restless leg syndrome; heart and lung diseases, acute and congestive heart failure; hypotension; hypertension; urinary retention; osteoporosis; angina pectoris; myocardial infarction; ischemic or hemorrhagic stroke; subarachnoid hemorrhage; ulcers; allergies; benign prostatic hypertrophy; chronic renal failure; renal disease; impaired glucose tolerance; migraine; hyperalgesia; pain; enhanced or exaggerated sensitivity to pain such as hyperalgesia, causalgia, and allodynia; acute pain; burn pain; atypical facial pain; neuropathic pain; back pain; complex regional pain syndrome I and II; arthritic pain; sports injury pain; pain related to infection, e.g. HIV, post-chemotherapy pain; post-stroke pain; post-operative pain; neuralgia; conditions associated with visceral pain such as irritable bowel syndrome, and angina; migraine; urinary bladder incontinence, e.g. urge incontinence; tolerance to narcotics or withdrawal from narcotics; sleep disorders; sleep apnea; narcolepsy; insomnia; parasomnia; jet lag syndrome; and neurodegenerative disorders including nosological entities such as disinhibition-dementia-parkinsonism-amyotrophy complex; pallido-ponto-nigral degeneration; epilepsy; seizure disorders and other diseases related to general orexin system dysfunction.
Some orexin receptor antagonists are capable of influencing at least some of the above described pathological conditions. In particular, orexin receptor antagonists capable of promoting sleep in animals and humans are described in the art. One example for such an orexin receptor antagonist is [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone which has the structure according to Formula I
and which is, e.g., described in US 2008/0132490, WO 2008/069997 and Cox et al. (2010) Journal of Medicinal Chemistry, 53(14): 5320-5332. Alternative names for this compound are 5-chloro-2-{(5R)-5-methyl-4-[5-methyl-2-(2H-1,2,3-thiazol-2-yl)benzoyl]-1,4-diazepan-1-yl}-1,3-benzobenzoxazol and [(R)-4-(5-chloro-benzooxazol-2-yl)-7-methyl-[1,4]diazepan-1-yl]-(5-methyl-2-[1,2,3]triazol-2-yl-phenyl)-methanone.
The synthesis of [(7R)-4-(5-chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl]methanone (herein also referred to as “Suvorexant” or “orexin receptor antagonist”) is described in WO 2008/069997. There, a synthesis that is based on a chiral resolution by chiral HPLC (high performance liquid chromatography) is described. The first step of this synthesis involves a 1,4-addition of Boc-ethylenediamine to methyl vinylketone followed by a Cbz-protection of the free amine to give a Boc-protected intermediate. The Boc-protecting group is then cleaved with HCl and a 7-membered ring is closed by a reductive amination reaction sequence to give a racemic compound which after re-protection of the free amine with a Boc-protective group is resolved by preparative chiral HPLC. The resulting enantiomerically pure amine is then coupled with a triazole benzoic acid derivative under standard peptide coupling conditions. Hydrogenation cleaves the Cbz-protecting group and the resulting amine is then finally coupled with a benzoxazole derivative to give Suvorexant. However, in this linear sequence a large number of steps is needed to provide Suvorexant with only rather low yields. Further, the synthesis is disadvantageous in that a chiral resolution by preparative HPLC is needed, a process which is costly and thus not suitable for the preparative scale.
A further synthesis of Suvorexant is described in WO 2012/148553. This process patent discloses a different route towards Suvorexant. According to WO 2012/148553, chloroaminophenol is condensed with thiophosgene to give mercaptobenzoxazole which is then converted into a ketone by treatment with oxalyl chloride/DMF followed by a one-pot reaction with mono Boc-protected ethylenediamine and vinylketone. The Boc-protecting group is then cleaved to give an intermediate which is then cyclized by a transfer hydrogenation with a costly and very specific ruthenium catalyst to give an enantiomerically pure compound comprising a free amine group. The amine is then coupled with the acid chloride of a triazole benzoic acid derivative to give Suvorexant.
A stereoselective Suvorexant synthesis includes a tandem enantioselective transamination/ring formation and is described in WO2013/169610. The synthesis starts with the preparation of a mesylate under standard conditions which is then converted into an amine in the presence of a (R)-selective sitagliptin transaminase and the intermediately formed amine cyclizes to give the seven-membered diazepane ring. This step requires a strict control of process parameters to suppress the formation of an undesired impurity (regioisomer). Further, a very specific and sensitive enzyme needs to be employed which again renders the process disadvantageous for the preparative scale.
Thus, there is still the need for an improved synthesis of Suvorexant which provides Suvorexant in high yields and which overcomes the disadvantages of the processes described in the prior art, such as the use of costly and complex catalyst systems and sensitive enzymes.